Abstract Subarachnoid hemorrhage (SAH) remains a serious source of neurological morbidity, with approximately 50,000 cases reported in the US each year. Despite advances in treating the initial and subsequent bleeds, post-surgical clipping of the aneurysm is associated with a significant risk of delayed cerebral ischemia (DCI). These events typically occur within the first 5-14 days after aneurysmal rupture and DCI remains the single most important cause of morbidity and mortality in those patients who survive the initial bleed. Additional medicines are needed since nimodipine, the only intervention approved for the condition, provides only 30-40% rescue from neurological and cognitive deficits, rendering SAH an important unmet clinical need. Preclinical evidence demonstrates that prolonged exposure of neurons to glutamate released during cerebral ischemia leads to cell death that is largely mediated through N-methyl-D-aspartate receptors (NMDARs). Inhibition of NMDA receptors including the GluN2B subtype greatly reduces neuronal damage due to brain ischemia. NP10679 is a highly selective, pH dependent inhibitor of the GluN2B subtype of the NMDAR with negligible activity at the other NMDAR subtypes. The property of pH dependence improves the chances of achieving efficacy at dose levels that limit untoward effects. The selectivity and specificity of NP10679 allows for prophylactic use in patients at risk for an ischemic event (i.e., following SAH). This is important because extensive data reveal most robust neuroprotection when NMDAR blockers are administered prior to the ischemic insult. The intended intervention strategy takes advantage of the prophylactic use of NP10679 in SAH driven DCI to avoid a time of dosing caveat that might, in part, have led to previous failures of clinical tests glutamatergic agents in stroke and head trauma. In August, FDA reviewed NeurOp's NP10679 IND application and informed NeurOp that it had opened the IND but placed it on clinical hold until final drug product would be manufactured. The safety/tolerability package along with the clinical plan and protocols used to support clinical development were accepted without comment. The studies proposed in the current grant application could lead to validation of pharmacologic neuroprotectant therapy in brain ischemia by qualifying NP10679 for future efficacy studies in phase II and III. We propose to manufacture enough NP10679 drug product to complete phase I clinical studies in order to remove the clinical hold on the IND. We will than proceed to single and multiple ascending dose studies in normal healthy volunteers with the goal of gathering all data and documentation to move on to phase II studies in SAH patients.